The project is a small program to develop a murine model for PKU and/or related diseases. Another objective is the elucidation of regulatory mechanisms in the expression of phenylalanine hydroxylation (PH). Criteria for a putative deficiency in PH were established: plasma phenylalanine levels, plasma phenylalanine-to-tyrosine (P/T) ratio, and hepatic levels of dihydropteridine reductase (DPR). Early results indicating that hepatic DPR in mice was not in great excess were contrary to generally accepted hypotheses. DPR insufficiency was expressed by mild symptoms of deficiency in PH. These findings pointed out inadequacies of standard programs for detecting heterozygote mouse PKU mutants. Murine DPR insufficiency was studied using mildly elevated P/T as a criterion. Putative mutant families were developed, but infertility and/or selective survival led to a loss of viable abnormal offspring at F4 or higher. Hepatic enzyme and cofactor patterns differed among the families, a reflection of the complex nature of PH. Current work elucidates the PH system in mice, shows the relationship of in vivo elevated P/T to in vitro measurable hepatic phenylalanine hydroxylase (PAH) using parachlorophenylalanine to inhibit PAH in vivo, and explores pharmacologically-induced murine models for dihydropteridine reductase deficiency.